The compound 4-[(3-{[4-(cyclopropylcarbonyl)-piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one, commonly known as Olaparib, is described in WO 2004/080976 A1. Olaparib, which is marketed in the United States as LYNPARZA®, is an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

Crystalline forms of Olaparib, including solvated and hydrated forms, are known, and have been disclosed, for example, in WO 2008/047082 A2, WO 2009/050469 A1, WO 2010/041051 A1, WO 2017/123156 A1, and WO 2017/140283 A1.
According to the European CHMP Assessment Report for LYNPARZA® (EMEA/H/C/003726/0000), the drug substance Olaparib in the approved drug product has both low solubility and low permeability, placing Olaparib in Class IV of the Biopharmaceutics Classification System (BCS). Of the four BCS Classes, owing to their low solubility and poor permeability, Class IV drug substances present the most challenges to achieving adequate bioavailability.
Approaches to improving the solubility of a drug substance include, for example, particle size reduction techniques, dispersion of the drug substance onto an inert carrier, and formulation of the drug substance together with solubilizing excipients. According to the CHMP report for LYNPARZA®, the drug substance Olaparib in the originally approved capsule form of LYNPARZA®, is micronized and formulated as a crystalline solid dispersion in lauroyl macrogol-32 glycerides (LMG) to optimize solubility and bioavailability. However, in order to maintain an optimal ratio of active substance to LMG, the percentage of Olaparib in each dosage of the drug product is very low, requiring a dosage regimen of 16 capsules having 50 mg strength daily to provide adequate plasma levels. Subsequent 100 mg and 150 mg tablet forms of Olaparib have since been approved in the United States that provide improved bioavailability and allow for a daily dose reduction from 800 mg to 600 mg that is also deliverable in fewer dose units. The development of 100 mg and 150 mg tablet forms of Olaparib is described in WO 2010/041051 A1, wherein the drug substance is present in an amorphous form as a dispersion with a matrix polymer such as copovidone. However, amorphous forms tend to have lower stability compared to crystalline forms, and methods for their preparation can be complex on an industrial scale. As a result, there remains a need for new crystalline forms of Olaparib providing a suitable dissolution profile without requiring micronization or the preparation of an amorphous form.
Different crystalline forms of the same compound may have different crystal packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different crystalline forms may have different stability properties such that a particular crystalline form may be less sensitive to heat, relative humidity (RH) and/or light. Alternatively or additionally, a particular crystalline form may provide more favourable compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing. Differences in stability between solid forms of a drug may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, including a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. Particular crystalline forms may also have different solubilities, thereby providing different pharmacokinetic parameters, which allow for specific crystalline forms to be used in order to achieve specific pharmacokinetic targets. Differences in solubility between crystalline forms are particularly relevant for compounds exhibiting low aqueous solubility, such as BCS Class IV drug substances such that even a modest increase in solubility may provide a beneficial enhancement in bioavailability.
Although general approaches to crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. For example, in the case of Olaparib, different crystalline forms can arise even when using the same preparation solvent or solvent mixture. As reported in WO 2009/050469 A1 and WO 2008/047082 A2, ethanol/water mixtures and methanol/water mixtures afford either Form A or Form L, which are both anhydrous forms. Furthermore, the use of water as the sole solvent can result in formation of hydrate, such as Form H as reported in WO 2010/041051 A1. Further examples of this dichotomy are reported with acetonitrile and acetic acid/water mixtures. Accordingly, it is not possible to extend generalities to the number and kinds of crystalline forms that can exist for Olaparib, or to what methods will be suitable for the preparation of any given crystalline form. Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).
Due to the classification of Olaparib as a BCS Class IV drug substance, and the prior need to provide Olaparib in a micronized form or as an amorphous material in order to provide suitable bioavailability, there exists a need for novel crystalline forms of Olaparib for use in providing drug products containing Olaparib and their manufacture.